Alunbrig (brigatinib)

Brigatinib, an inhibitor of multiple tyrosine kinases, including anaplastic lymphoma kinase (ALK), is an antineoplastic agent.

Brigatinib, an inhibitor of multiple tyrosine kinases, including anaplastic lymphoma kinase (ALK), c-ros oncogene-1 (ROS-1), insulin-like growth factor receptor-1 (IGFR-1), and fms-like tyrosine kinase 3 (FLT-3) as well as epidermal growth factor receptor (EGFR) deletion and point mutations, is an antineoplastic agent. The drug inhibits autophosphorylation of ALK and ALK-mediated phosphorylation of the downstream signaling proteins signal transducer and activator of transcription 3 (STAT3), AKT serine/threonine kinase, extracellular signal-regulated kinase (ERK) 1/2, and ribosomal protein S6 in vitro and in vivo.

Activating mutations or translocations of the ALK gene have been identified in several malignancies and can result in the expression of oncogenic fusion proteins (e.g., echinoderm microtubule-associated protein-like 4 (EML4)-ALK). Such ALK gene rearrangements have been identified in approximately 3-7% of patients with non-small cell lung cancer (NSCLC). Formation of ALK fusion proteins such as EML4-ALK results in activation and dysregulation of the gene's expression and signaling, which can contribute to increased cell proliferation and survival in tumors expressing these proteins.

Although the ALK inhibitor crizotinib has demonstrated improved outcomes in patients with NSCLC harboring ALK mutations, secondary resistance to crizotinib eventually develops, generally within the first 1-2 years of treatment. Clinical resistance to crizotinib has been attributed to several possible mechanisms, including acquired resistance mutations of ALK, amplification of gene expression, and activation of alternate signaling pathways. Secondary mutations of ALK are responsible for about 30% of cases of acquired crizotinib resistance and gene amplification is implicated in 9% of these cases.

The CNS is a common site of disease progression in crizotinib-treated patients because of poor distribution of the drug into CSF; development and/or progression of brain metastases occurs in approximately one-half of patients during crizotinib treatment.

In vitro, brigatinib is approximately 12-fold more potent than crizotinib in its activity against native ALK-positive cell lines and is active against cell lines expressing EML4-ALK and nucleophosmin (NPM)-ALK fusion proteins and many mutant forms associated with resistance to alectinib, ceritinib, and/or crizotinib, as well as EGFR-Del (E746-A750), ROS1-L2026M, FLT3-F691L, and FLT3-D835Y. Brigatinib also demonstrated dose-dependent antitumor activity in mice bearing NSCLC tumor xenografts that expressed EML4-ALK, including those with the crizotinib resistance-conferring L1196M mutation and the G1202R mutation that also confers resistance to ceritinib and alectinib. In addition, brigatinib reduced tumor burden and prolonged survival in mice bearing intracranial ALK-positive NSCLC tumor xenografts.

Brigatinib also has demonstrated antitumor activity in patients with crizotinib-resistant disease and baseline CNS metastases.

Systemic exposure to brigatinib is dose proportional over the oral dosage range of 60-240 mg following single or multiple doses. Following oral administration, peak plasma concentrations of brigatinib are achieved in 1-4 hours. Administration of brigatinib with a high-fat meal decreases peak plasma concentrations of brigatinib by 13% but has no effect on systemic exposure compared with administration in the fasting state.

Brigatinib is 66% bound to plasma proteins and binding is independent of drug concentration. Brigatinib is primarily metabolized by cytochrome P-450 (CYP) isoenzymes 2C8 and 3A4; its major active metabolite, AP26123, inhibits ALK with approximately threefold lower potency than the parent drug. Steady-state systemic exposure of AP26123 is less than 10% of the parent drug.

Following oral administration of radiolabeled brigatinib, 65% of the dose is eliminated in feces (41% as unchanged drug) and 25% of the dose is eliminated in urine (86% as unchanged drug). The mean elimination half-life of brigatinib is 25 hours. Age, gender, race, body weight, and serum albumin concentration do not have clinically important effects on the pharmacokinetics of brigatinib.

USES: Brigatinib is used to treat a certain type of lung cancer (non-small cell lung cancer). It works by slowing or stopping the growth of cancer cells.

Generic name: brigatinib
Pronunciation: (bri-GA-ti-nib)

The following indications are listed for Alunbrig:

• Anaplastic Lymphoma Kinase Positive Non-Small Cell Lung Cancer

Also known as: Alk Positive Nsclc.

No ICD codes are available for this drug.